Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits

Tachibana, Tsuyoshi; Shiiya, Norihiko; Kunihara, Takashi; Wakamatsu, Yutaka; Kudo, Akimaro Fabio; Ōoka, Tomonori; Watanabe, Satoshi; Yasuda, Keishu

doi:10.1016/j.jtcvs.2004.04.047

Cited by 16 publications

(9 citation statements)

References 17 publications

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“…Our data indicate the existence of cross talk between the action of 0.25 -1 µM CsA as well as 1 µM FK506 on cPLA 2 and CaN in anti-apoptotic signal transduction pathways. Moreover, we have shown that immunophilin ligands at these concentrations protected glial cells against ischemia-induced apoptosis, as evidenced by the increase of cell viability, mitochondrial function restoration, and attenuation of oxidative stress.…”

Section: +mentioning

confidence: 64%

Inhibition of Arachidonic Acid Release by Cytosolic Phospholipase A2 Is Involved in the Antiapoptotic Effect of FK506 and Cyclosporin A on Astrocytes Exposed to Simulated Ischemia In Vitro

Gabryel¹,

Chalimoniuk²,

Stolecka³

et al. 2006

J Pharmacol Sci

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Section: +mentioning

confidence: 64%

Inhibition of Arachidonic Acid Release by Cytosolic Phospholipase A2 Is Involved in the Antiapoptotic Effect of FK506 and Cyclosporin A on Astrocytes Exposed to Simulated Ischemia In Vitro

Gabryel¹,

Chalimoniuk²,

Stolecka³

et al. 2006

J Pharmacol Sci

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“…Recently, it has been reported that both FK506 and CsA are effective in reducing injury in rabbit spinal cord ischemia/ reperfusion models. This suggests that in neural tissue the calcineurin-inhibiting property of CsA is the protective mechanism [19]. …”

Section: Commentmentioning

confidence: 99%

Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition

Leshnower

Kanemoto

Matsubara

et al. 2008

The Annals of Thoracic Surgery

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Background Opening of the mitochondrial permeability transition pore (MPTP) has been shown to contribute to myocardial ischemia/reperfusion injury. We sought to demonstrate that the myocardial protective effect of inhibiting MPTP opening with cyclosporine A (CsA) results in stabilization of mitochondrial morphology and is independent of CsA-induced calcineurin inhibition. Methods Thirty-seven rabbits were divided into three groups: control (n = 15), CsA (MPTP and calcineurin inhibitor, n = 12), or FK506 (calcineurin inhibitor, n = 10). Each group received a 1-hour infusion of either a saline vehicle, 25 mg/kg CsA or 1 mg/kg FK506. All animals underwent 30 minutes of regional ischemia and 3 hours of reperfusion. Myocardial infarct size was determined using Evans blue dye and triphenyltetrazolium chloride. In situ oligo ligation was used to assess apoptotic cell death. Transmission electron microscopy was used to quantitatively evaluate morphologic differences in the mitochondria between groups. Results Infarct size in the CsA group (39% ± 3%) was significantly reduced compared with the control group (60% ± 2%, p < 0.001) and FK506 group (55% ± 3%, p = 0.001). Apoptotic cell death was also attenuated in the CsA group (1.2% ± 0.5%) compared with the control group (4.3% ± 0.8%, p = 0.01) and FK506 group (4.1% ± 0.9%, p = 0.05). Transmission electron microscopy revealed a preservation of normal mitochondrial morphology and a reduction in the percentage of disrupted mitochondria in the CsA group (20% ± 7%) compared with the control group (53% ± 12%) and FK506 group (47% ± 9%). Conclusions Cyclosporine A–induced MPTP inhibition preserves mitochondrial morphology after myocardial ischemia/reperfusion and limits myocyte necrosis and apoptosis. These effects are independent of calcineurin inhibition.

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“…Binding of FK506 to FKBP12 led to forming a complex, which inhibits calcineurin (Liu et al 1991); this in turn, would be expected to increase the amount of the active form of the growthassociated protein GAP-43 in neurons (Bavetta et al 1999). In relevant studies were shown, that FK506 offered neuroprotection following brain and spinal cord ischemia (Benetoli et al 2007;Furuichi et al 2003;Tachibana et al 2005;Tokime et al 1996;Yagita et al 1996), traumatic brain (Marmarou and Povlishock 2006;Reeves et al 2007), and spinal cord injury (Lopez-Vales et al 2006;Madsen et al 1998;Nottingham et al 2002;Voda et al 2005Voda et al , 2007. However, FK506 effectiveness varied depending on model of CNS injury and FK506 regimen.…”

Section: Introductionmentioning

confidence: 99%

Effects of Long-Term FK506 Administration on Functional and Histopathological Outcome after Spinal Cord Injury in Adult Rat

et al. 2009

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FK506 (tacrolimus), a potent immunosuppressive drug primarily used for reduction of allograft rejection in organ transplantation, also offers neuroprotection after central nervous system injury. FK506-mediated immunosuppression and neuroprotection may occur through different mechanisms that could affect neurological recovery and the severity of spinal lesions where cells transplantation therapy is combined with FK506 application. We assessed effects of long-term FK506 administration using the same dose regiment (1 mg/kg/day for 6 weeks) as is used in spinal cord transplantation studies following a balloon-compression induced spinal cord injury (SCI). Body weight and locomotor recovery quantified by the BBB (Basso-Beattie-Bresnehan) locomotor rating scale were evaluated for up to 42 days post-injury. The area of the preserved spinal cord tissue within a 13 mm segment of the spinal cord (lesion epicenter and 6 mm rostral-caudal) was examined histologically. The results showed no significant effects of FK506 on spinal cord tissue sparing or improvement of locomotor recovery. However, body weight fell significantly (P < 0.05) with FK506 treatment when compared with placebo from day 7 until sacrifice. In our experimental design, long-term FK506 treatment did not affect the parameters of outcome following balloon-compression SCI in the rat; however, multiple effects of FK506 should be taken into account when evaluating the outcomes in transplantation studies.

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Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits

Cited by 16 publications

References 17 publications

Inhibition of Arachidonic Acid Release by Cytosolic Phospholipase A2 Is Involved in the Antiapoptotic Effect of FK506 and Cyclosporin A on Astrocytes Exposed to Simulated Ischemia In Vitro

Inhibition of Arachidonic Acid Release by Cytosolic Phospholipase A2 Is Involved in the Antiapoptotic Effect of FK506 and Cyclosporin A on Astrocytes Exposed to Simulated Ischemia In Vitro

Cyclosporine Preserves Mitochondrial Morphology After Myocardial Ischemia/Reperfusion Independent of Calcineurin Inhibition

Effects of Long-Term FK506 Administration on Functional and Histopathological Outcome after Spinal Cord Injury in Adult Rat

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